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Mass Spectrometry and Luminogenic-based Approaches to Characterize Phase I Metabolic Competency of In Vitro Cell Cultures
Published on: March 28, 2017
Mechanistic study of bergamottin-induced inactivation of CYP2C9
Ying Liu1, Shiyu Zhang1, Tingting Jiang1
1State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Provincial Key Laboratory of Pharmaceutics, Guizhou Medical University, Guiyang, 550004, Guizhou, PR China; School of Pharmacy, Guizhou College Medical University, Guiyang, 550004, Guizhou, PR China.
Abstract:
Bergamottin (BGM) is a major furanocoumarin constituent of grapefruit and is reported to have inhibitory effects on cytochrome P450 enzymes. This study investigated the chemical interactions between BGM and the enzyme CYP2C9. BGM exhibited time-, concentration-, and NADPH-dependent inhibition of CYP2C9. Co-incubation with diclofenac, a reversible inhibitor of CYP2C9, attenuated the time-dependent enzyme inhibition. Exhaustive dialysis did not restore enzyme activity post-inhibition. Glutathione (GSH) and catalase/superoxide dismutase failed to reverse BGM-induced CYP2C9 inactivation. A GSH trapping study suggested that BGM was metabolized to an epoxide and/or γ-ketoenal that may have been responsible for the enzyme inactivation. In conclusion, BGM can be characterized as a mechanism-based inactivator of CYP2C9 acting via the formation of an epoxide and/or γ-ketoenal.
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